Deep intronic 9q21.11 polymorphism contributes to atopic dermatitis risk through methylation regulated expression of tight junction protein 2.

BACKGROUND AND OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory itchy skin condition. Genomic- and epigenetic wide association studies provide insights into the genetic susceptibility and potential underlying disease pathogenesis. This study sought to functionally characterise an AD-associated single nucleotide polymorphism (SNP) located deep intronic of the tight junction protein 2 (TJP2) gene (9q21.11 locus), identified through a genome-wide association study (GWAS). METHODS: The association between the 9q21.11 locus (rs7872806) and AD was identified through a GWAS of 956 cases and 723 controls. TJP2 expression in peripheral blood mononuclear cells (PBMCs) was assessed against the rs7872806 genotypes. Allele-specific methylation was evaluated at CpG sites 10kb up- and down-stream of the 9q21.11 locus. Effects of DNA methylation on TJP2 expression was validated via in vitro methylation and 5-aza-2'-deoxycytidine-induced transcriptional activation studies. Trans-epidermal water loss measurements were used to determine skin barrier function. RESULTS: The major allele of rs7872806 was determined to increase AD risk by 2.64-fold (adjusted p-value=2.40 x 10-18, OR=0.38), associated with increased methylation levels at cg13920460 site (p<0.001) and lower TJP2 expression in PBMCs (Pearson's p=1.09 x 10-6, Pearson's R=-0.313, p<0.001). Methylation inhibition by 5-aza-2'-deoxycytidine increased TJP2 promoter activity by up to 85%. Elimination of the cg13920460 methylation site increased expression by approximately 25%. The rs7872806 major allele was also found to be associated with increased trans-epidermal water loss (p<0.001). CONCLUSION: Epigenetic influence at CpG site cg13920460 is associated with rs7872806 located deep intronic at 9q21.11. The SNP confers susceptibility to AD through altering TJP2 expression and promoting trans-epidermal water loss.

Laponite-Based Nanomaterials for Drug Delivery.

Laponite is a clay-based material composed of synthetic disk-shaped crystalline nanoparticles with highly ionic, large surface area. These characteristics enable the intercalation and dissolution of biomolecules in Laponite-based drug delivery systems. Furthermore, Laponite's innate physicochemical properties and architecture enable the development of tunable pH-responsive drug delivery systems. Laponite's coagulation capacity and cation exchangeability determine its exchange capabilities, drug encapsulation efficiency, and release profile. These parameters are exploited to design highly controlled and efficacious drug delivery platforms for sustained drug release. In this review, they provide an overview of how to design efficient delivery of therapeutics by leveraging the properties and specific interactions of various Laponite-polymer composites and drug moieties.

The Ophthalmology Chief Resident: Does Surgical Volume Correlate With Likelihood of Selection?

PURPOSE: Investigate whether number of logged Accreditation Council for Graduate Medical Education (ACGME) surgical cases correlates with likelihood of Virginia Commonwealth University Health System (VCUHS) ophthalmology residents being selected as the chief resident. DESIGN: Retrospective study. PARTICIPANTS: VCUHS ophthalmology residents from 2006 to 2016. METHODS: Analyze association between chief resident selection and logged cases. MAIN OUTCOME MEASURES: Review number of archived logged ACGME surgical cases of all residents between the years 2006 and 2017. Review chief resident selected each year 2006-2016. RESULTS: Our analysis correctly predicted the chief resident in 2 of the 10 years analyzed. CONCLUSION: Those residents performing the most surgical procedures in each respective class were not more likely to be selected as chief resident.

Systemically Administered Hemostatic Nanoparticles for Identification and Treatment of Internal Bleeding.

Internal bleeding is an injury that can be difficult to localize and effectively treat without invasive surgeries. Injectable polymeric nanoparticles have been developed that can reduce clotting times and blood loss, but they have yet to incorporate sufficient diagnostic capabilities to assist in identifying bleeding sources. Herein, polymeric nanoparticles were developed to simultaneously treat internal bleeding while incorporating tracers for visualization of the nanoparticles by standard clinical imaging modalities. Addition of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD; a fluorescent dye), biotin functionality, and gold nanoparticles to hemostatic polymeric nanoparticles resulted in nanoparticles amenable to imaging with near-infrared (NIR) imaging, immunohistochemistry, and X-ray computed tomography (CT), respectively. Following a lethal liver resection injury, visualization of accumulated nanoparticles by multiple imaging methods was achieved in rodents, with the highest accumulation observed at the liver injury site, resulting in improved survival rates. Tracer addition to therapeutic nanoparticles allows for an expansion of their applicability, during stabilization by first responders to diagnosis and identification of unknown internal bleeding sites by clinicians using standard clinical imaging modalities.

Endovascular Embolization by Transcatheter Delivery of Particles: Past, Present, and Future.

Minimally invasive techniques to occlude flow within blood vessels, initially pioneered in the 1970s with autologous materials and subsequently advanced with increasingly sophisticated engineered biomaterials, are routinely performed for a variety of medical conditions. Contemporary interventional radiologists have at their disposal a wide armamentarium of occlusive agents to treat a range of disease processes through a small incision in the skin. In this review, we provide a historical perspective on endovascular embolization tools, summarize the current state-of-the-art, and highlight burgeoning technologies that promise to advance the field in the near future.

Classical Challenges in the Physical Chemistry of Polymer Networks and the Design of New Materials.

Polymer networks are widely used from commodity to biomedical materials. The space-spanning, net-like structure gives polymer networks their advantageous mechanical and dynamic properties, the most essential factor that governs their responses to external electrical, thermal, and chemical stimuli. Despite the ubiquity of applications and a century of active research on these materials, the way that chemistry and processing interact to yield the final structure and the material properties of polymer networks is not fully understood, which leads to a number of classical challenges in the physical chemistry of gels. Fundamentally, it is not yet possible to quantitatively predict the mechanical response of a polymer network based on its chemical design, limiting our ability to understand and characterize the nanostructure of gels and rationally design new materials. In this Account, we summarize our recent theoretical and experimental approaches to study the physical chemistry of polymer networks. First, our understanding of the impact of molecular defects on topology and elasticity of polymer networks is discussed. By systematically incorporating the effects of different orders of loop structure, we develop a kinetic graph theory and real elastic network theory that bridge the chemical design, the network topology, and the mechanical properties of the gel. These theories show good agreement with the recent experimental data without any fitting parameters. Next, associative polymer gel dynamics is discussed, focusing on our evolving understanding of the effect of transient bonds on the mechanical response. Using forced Rayleigh scattering (FRS), we are able to probe diffusivity across a wide range of length and time scales in gels. A superdiffusive region is observed in different associative network systems, which can be captured by a two-state kinetic model. Further, the effects of the architecture and chemistry of polymer chains on gel nanostructure are studied. By incorporating shear-thinning coiled-coil protein motifs into the midblock of a micelle-forming block copolymer, we are able to responsively adjust the gel toughness through controlling the nanostructure. Finally, we review the development of novel application-oriented materials that emerge from our enhanced understanding of gel physical chemistry, including injectable gel hemostats designed to treat internal wounds and engineered nucleoporin-like polypeptide (NLP) hydrogels that act as biologically selective filters. We believe that the fundamental physical chemistry questions articulated in this Account will provide inspiration to fully understand the design of polymer networks, a group of mysterious yet critically important materials.

An injectable shear-thinning biomaterial for endovascular embolization.

Improved endovascular embolization of vascular conditions can generate better patient outcomes and minimize the need for repeat procedures. However, many embolic materials, such as metallic coils or liquid embolic agents, are associated with limitations and complications such as breakthrough bleeding, coil migration, coil compaction, recanalization, adhesion of the catheter to the embolic agent, or toxicity. Here, we engineered a shear-thinning biomaterial (STB), a nanocomposite hydrogel containing gelatin and silicate nanoplatelets, to function as an embolic agent for endovascular embolization procedures. STBs are injectable through clinical catheters and needles and have hemostatic activity comparable to metallic coils, the current gold standard. In addition, STBs withstand physiological pressures without fragmentation or displacement in elastomeric channels in vitro and in explant vessels ex vivo. In vitro experiments also indicated that STB embolization did not rely on intrinsic thrombosis as coils did for occlusion, suggesting that the biomaterial may be suitable for use in patients on anticoagulation therapy or those with coagulopathy. Using computed tomography imaging, the biomaterial was shown to fully occlude murine and porcine vasculature in vivo and remain at the site of injection without fragmentation or nontarget embolization. Given the advantages of rapid delivery, in vivo stability, and independent occlusion that does not rely on intrinsic thrombosis, STBs offer an alternative gel-based embolic agent with translational potential for endovascular embolization.

Toughening of Thermoresponsive Arrested Networks of Elastin-Like Polypeptides To Engineer Cytocompatible Tissue Scaffolds.

Formulation of tissue engineering or regenerative scaffolds from simple bioactive polymers with tunable structure and mechanics is crucial for the regeneration of complex tissues, and hydrogels from recombinant proteins, such as elastin-like polypeptides (ELPs), are promising platforms to support these applications. The arrested phase separation of ELPs has been shown to yield remarkably stiff, biocontinuous, nanostructured networks, but these gels are limited in applications by their relatively brittle nature. Here, a gel-forming ELP is chain-extended by telechelic oxidative coupling, forming extensible, tough hydrogels. Small angle scattering indicates that the chain-extended polypeptides form a fractal network of nanoscale aggregates over a broad concentration range, accessing moduli ranging from 5 kPa to over 1 MPa over a concentration range of 5-30 wt %. These networks exhibited excellent erosion resistance and allowed for the diffusion and release of encapsulated particles consistent with a bicontinuous, porous structure with a broad distribution of pore sizes. Biofunctionalized, toughened networks were found to maintain the viability of human mesenchymal stem cells (hMSCs) in 2D, demonstrating signs of osteogenesis even in cell media without osteogenic molecules. Furthermore, chondrocytes could be readily mixed into these gels via thermoresponsive assembly and remained viable in extended culture. These studies demonstrate the ability to engineer ELP-based arrested physical networks on the molecular level to form reinforced, cytocompatible hydrogel matrices, supporting the promise of these new materials as candidates for the engineering and regeneration of stiff tissues.

Thermoresponsive and Mechanical Properties of Poly(L-proline) Gels.

Gelation of the left helical N-substituted homopolypeptide poly(L-proline) (PLP) in water was explored, employing rheological and small-angle scattering studies at different temperatures and concentrations in order to investigate the network structure and its mechanical properties. Stiff gels were obtained at 10 wt % or higher at 5 °C, the first time gelation has been observed for homopolypeptides. The secondary structure and helical rigidity of PLP has large structural similarities to gelatin but as gels the two materials show contrasting trends with temperature. With increasing temperature in D2O, the network stiffens, with broad scattering features of similar correlation length for all concentrations and molar masses of PLP. A thermoresponsive transition was also achieved between 5 and 35 °C, with moduli at 35 °C higher than gelatin at 5 °C. The brittle gels could tolerate strains of 1% before yielding with a frequency-independent modulus over the observed range, similar to natural proline-rich proteins, suggesting the potential for thermoresponsive or biomaterial-based applications.

A Highly Elastic and Rapidly Crosslinkable Elastin-Like Polypeptide-Based Hydrogel for Biomedical Applications.

Elastin-like polypeptides (ELPs) are promising for biomedical applications due to their unique thermoresponsive and elastic properties. ELP-based hydrogels have been produced through chemical and enzymatic crosslinking or photocrosslinking of modified ELPs. Herein, a photocrosslinked ELP gel using only canonical amino acids is presented. The inclusion of thiols from a pair of cysteine residues in the ELP sequence allows disulfide bond formation upon exposure to UV light, leading to the formation of a highly elastic hydrogel. The physical properties of the resulting hydrogel such as mechanical properties and swelling behavior can be easily tuned by controlling ELP concentrations. The biocompatibility of the engineered ELP hydrogels is shown in vitro as well as corroborated in vivo with subcutaneous implantation of hydrogels in rats. ELP constructs demonstrate long-term structural stability in vivo, and early and progressive host integration with no immune response, suggesting their potential for supporting wound repair. Ultimately, functionalized ELPs demonstrate the ability to function as an in vivo hemostatic material over bleeding wounds.

Shear-thinning nanocomposite hydrogels for the treatment of hemorrhage.

Internal hemorrhaging is a leading cause of death after traumatic injury on the battlefield. Although several surgical approaches such as the use of fibrin glue and tissue adhesive have been commercialized to achieve hemostasis, these approaches are difficult to employ on the battlefield and cannot be used for incompressible wounds. Here, we present shear-thinning nanocomposite hydrogels composed of synthetic silicate nanoplatelets and gelatin as injectable hemostatic agents. These materials are demonstrated to decrease in vitro blood clotting times by 77%, and to form stable clot-gel systems. In vivo tests indicated that the nanocomposites are biocompatible and capable of promoting hemostasis in an otherwise lethal liver laceration. The combination of injectability, rapid mechanical recovery, physiological stability, and the ability to promote coagulation result in a hemostat for treating incompressible wounds in out-of-hospital, emergency conditions.

Bearing surfaces for hip arthroplasty - is metal-on-metal a passing fancy?

Metal-on-metal bearings have had popularity that has waxed and waned over the years. The advantages realized relative to wear resistance and strength had been offset by early failures, manufacturing difficulty, and most recently by adverse soft tissue responses to the metallic debris. The bearing's history, evolution, advantages and disadvantages will be discussed in attempt to answer the question: is metal-on-metal a passing fancy?

Comparison of surface characteristics of retrieved cobalt-chromium femoral heads with and without ion implantation.

Nitrogen ion implantation of CoCr is reported to produce increased surface hardness and a lower friction surface. Femoral heads with and without ion implantation retrieved from 1997 to 2003 were evaluated for surface roughness (average surface roughness [Ra], mean peak height [Rpm], and maximum distance from peak to valley [Rmax]), nanohardness, and the ion-treated layer thickness. The difference in average Rmax (P = .033) and average Rpm (P = .008) was statistically significant, but there was no correlation between the average or maximum roughness parameters (average surface roughness, Rmax, and Rpm) and time in vivo (P > .05). Overall, nanohardness was greater for the low-friction ion-treated heads (P < .001); and it decreased with increasing time in vivo (P = .01). Ion treatment produces an increased surface hardness, but the advantage of this increased hardness appears to dissipate over time in vivo.

Immunoglobulin E antibody reactivity to bacterial antigens in atopic dermatitis patients.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting up to 20% children and 9% adults world-wide. AD patients are often sensitized against a broad variety of allergens and more than 90% of them suffer from skin superinfections with Staphylococcus aureus. OBJECTIVE: In this study, we searched for the presence of specific IgE antibodies against S. aureus and Escherichia coli antigens in AD patients. METHODS: Sera from AD patients (n=79), patients suffering only from allergic rhinoconjunctivitis (n=41) or allergic asthma (n=37) were tested for IgE reactivity to nitrocellulose-blotted S. aureus, E. coli and gut bacterial antigens. IgE-reactive bacterial antigens were affinity purified and identified by mass spectrometry. RESULTS: More than 30% of AD patients but not patients suffering only from allergic rhinoconjunctivitis and asthma or non-allergic persons exhibited IgE binding to several protein antigens among them DNA-binding and ribosomal proteins and flagellin. Patients with severe skin manifestations showed more frequently IgE reactivity to S. aureus compared with AD patients with mild symptoms. Positive immediate and late skin test reactions could be induced in sensitized AD patients with S. aureus extract. CONCLUSION AND CLINICAL RELEVANCE: Specific IgE reactivities against a variety of bacterial antigens were observed in a subgroup comprising a third of AD patients and may contribute to allergic inflammation.

Metal-on-metal bearings: the problem is edge-loading wear.

Metal-on-metal bearings are promoted as a low wear bearing alternative to traditional hip replacement bearings. While most in vitro studies support this, recent clinical reviews have found a significant number of early revisions in some designs of metal-on-metal bearings related to wear. Metal-on-metal bearings exhibit a bi-phasic wear pattern with high initial wear that generally settles down to low steady state wear. Previous publications from the authors have found that steady state wear occurs due to the formation of a critical conforming contact area. This contact area was found to be surprisingly constant regardless of bearing size, clearance, or even contact mode. The authors hypothesized that steady state wear may never be reached if formation of this critical conforming contact area is disrupted. Several hip simulator tests were performed to assess the wear performance of generic metal-on-metal samples at various angles of inclination. Three-dimensional modeling was performed on the generic bearing design as well as typical resurfacing and hemispherical bearing designs including various sizes and clearance ranges. Simulator results support the hypotheses, and wear rates were linear or accelerating when the critical contact area size could not be achieved due to its proximity to the rim of the bearing. Modeling studies show a correlation between bearing size and design and the maximum inclination angle allowed to reach steady state conditions. Smaller bearing size and shallower cup designs were found to reduce the maximum safe inclination angle and this corresponds to clinical observation of increased failure rates in these bearings. This simple method for assessing runaway wear risk can be utilized in the design of more robust and forgiving metal-on-metal bearings.

The hazards of gastric lavage for intentional self-poisoning in a resource poor location.

OBJECTIVE: The 10-20% case fatality found with self-poisoning in the developing world differs markedly from the 0.5% found in the West. This may explain in part why the recent movement away from the use of gastric lavage in the West has not been followed in the developing world. After noting probable harm from gastric lavage in Sri Lanka, we performed an observational study to determine how lavage is routinely performed and the frequency of complications. CASE SERIES: Fourteen consecutive gastric lavages were observed in four hospitals. Lavage was given to patients unable or unwilling to undergo forced emesis, regardless of whether they gave consent or the time elapsed since ingestion. It was also given to patients who had taken non-lethal ingestions. The airway was rarely protected in patients with reduced consciousness, large volumes of fluid were given for each cycle (200 to more than 1000 ml), and monitoring was not used. Serious complications likely to be due to the lavage were observed, including cardiac arrest and probable aspiration of fluid. Health care workers perceived lavage as being highly effective and often life-saving; there was peer and relative pressure to perform lavage in self-poisoned patients. CONCLUSIONS: Gastric lavage as performed for highly toxic poisons in a resource-poor location is hazardous. In the absence of evidence for patient benefit from lavage, (and in agreement with some local guidelines), we believe that lavage should be considered for few patients - in those who have recently taken a potentially fatal dose of a poison, and who either give their verbal consent for the procedure or are sedated and intubated. Ideally, a randomized controlled trial should be performed to determine the balance of risks and benefits of safely performed gastric lavage in this patient population.

Patterns of hospital transfer for self-poisoned patients in rural Sri Lanka: implications for estimating the incidence of self-poisoning in the developing world.

OBJECTIVES: Most data on self-poisoning in rural Asia have come from secondary hospitals. We aimed to: assess how transfers from primary to secondary hospitals affected estimates of case-fatality ratio (CFR); determine whether there was referral bias according to gender or poison; and estimate the annual incidence of all self-poisoning, and of fatal self-poisoning, in a rural developing-world setting. METHODS: Self-poisoning patients admitted to Anuradhapura General Hospital, Sri Lanka, were reviewed on admission from 1 July to 31 December 2002. We audited medical notes of self-poisoning patients admitted to 17 of the 34 surrounding peripheral hospitals for the same period. FINDINGS: A total of 742 patients were admitted with self-poisoning to the secondary hospital; 81 died (CFR 10.9%). 483 patients were admitted to 17 surrounding peripheral hospitals. Six patients (1.2%) died in peripheral hospitals, 249 were discharged home, and 228 were transferred to the secondary hospital. There was no effect of gender or age on likelihood of transfer; however, patients who had ingested oleander or paraquat were more likely to be transferred than were patients who had taken organophosphorus pesticides or other poisons. Estimated annual incidences of self-poisoning and fatal self-poisoning were 363 and 27 per 100,000 population, respectively, with an overall CFR of 7.4% (95% confidence interval 6.0-9.0). CONCLUSION: Fifty per cent of patients admitted to peripheral hospitals were discharged home, showing that CFRs based on secondary hospital data are inflated. However, while incidence of self-poisoning is similar to that in England, fatal self-poisoning is three times more common in Sri Lanka than fatal self-harm by all methods in England. Population based data are essential for making international comparisons of case fatality and incidence, and for assessing public health interventions.